Salt formation is an acid-base reaction involving either a proton-transfer or neutralization reaction and is therefore controlled by factors influencing such reactions. Theoretically, every compound that exhibits acid or base characteristics can participate in salt formation. Particularly important is the relative strength of the acid or base and the acidity and basicity constants of the chemical species involved. These factors determine whether or not salt formation occurs and are a measure of the stability of the resulting salt. The salt form is known to influence a number of physico-chemical properties of the parent compound including dissolution rate, solubility, stability, and hygroscopicity. Salt formation is useful in pharmaceutical formulations since these properties, in turn, affect the availability and formulation characteristics of the drug.
Higuchi et al. Anal. Chem. 39; 974-979 (1967) discloses the physicochemical basis behind the ion-pair extraction of pharmaceutical amines and suggests the use of ion-pairing for the improvement of drug lipophilicity and absorption. European patent 96,013 to Casini et al. discloses the preparation of novel salts of Erythromycin A with acetylsalicylic acid that has antipyretic and anti-inflammatory activity and with DL-alpha mercaptopropionyl glycine with mucolytic and hepatoprotective activity. These compounds allegedly have the pharmacological activity of the antibiotic moiety as well as that of the acidic moiety. These new salts also allegedly have physico-chemical properties different from both erythromycin A and the acidic moeity.
French patent no. 1,479,209 discloses codeine acytylsalicylate as a new salt having analgesic, anti-inflammatory and cough suppressant activities that also modifies bronchial secretions. U.S. Pat. Nos. 4,816,247 to Desai et al and 4,515,811 to Halton et al. disclose pharmaceutical applications of salt formation. U.S. Pat. Nos. 4,563,443 to Gobetti et al. and 4,521,538 to Baglioni et al. disclose new derivatives of known drugs by the formation of ester and thioester linkages of known compounds. Japanese patent no. 13273/65 discloses a salt of glycyrrhetic acid with beta-dimethyl aminoethyl benzhydryl ether with allegedly greater anti-inflammatory and antihistamine activities than its individual pharmaceutical components. The compounds dissolve slowly in acid and alkali thus giving sustained release action of the active component upon oral administration.
For purposes of this disclosure, the term salt/ion pair is used to refer to the fact that the new chemical entities produced by the acid-base reaction exists in either the solid crystalline form "salt" or as an amorphous, semi-solid viscous mass "ion-pair".
It is an object of the present invention to prepare novel salts of non-steroidal anti-inflammatory agents together with an antihistamine, sympathomimetic drug, cough suppressant or expectorant together with a pharmaceutically acceptable, non-toxic carrier. These novel pharmaceutical compositions allow for the use of a single new compound in place of the physical mixtures of several compounds found in the prior art. The novel pharmaceutical compositions also possess solubilities different from those of the individual drug components which enables the easier preparation of sustained or enhanced release dosage forms. And surprisingly, the compounds of the present invention do not exhibit the pharmaceutical incompatabilities expected when the sodium salt of an anti-inflammatory drug is combined with the strong acid salts of an antihistamine.
It is a further object of the present invention to prepare novel salts/ion pairs of non-steroidal anti-inflammatory drugs with non-sedating antihistamines and decongestants with unique physico-chemical properties over the multi-symptom relief medicines known in the art. Specifically, non-steroidal anti-inflammatory drugs such as meclofenamic acid, salicylic acid, ibuprofen, naproxen, dichlofinac, sulindac and aspirin are used to form novel salt/ion pairs with antihistamines and decongestants such as Diphenhydramine, Pseudoephedrine, Hismanal, Terfenadine, Loratidine, Ranitidine, Cimetidine, etc.
Meclofenamic acid is an antiflammatory and antipyretic compound with the following formula: ##STR1##
Naproxen is a non-steroidal, anti-inflammatory analgesic and antipyretic with the following formula: ##STR2##
Sulindac is also an anti-inflammatory drug with the following structure: ##STR3##
Salicylic acid is a topical keratolytic with the following structure: ##STR4##
Ibuprofen is a non-steroidal anti-inflammatory compound with the following structure: ##STR5##
Diphenhydramine, Pseudoephedrine, Hismanal and Terfenidine are all antihistamines with the following respective formulas: ##STR6##